For most infected individuals, HIV leads inexorably to CD4+ T cell depletion and profound immunodeficiency. For a fortunate few HIV infection results in extremely limited viral replication and peripheral CD4+ T cell counts are maintained. These patients, termed 'Elite Controllers', have been subject to intensive study since understanding how they control the virus should inform the vaccine effort. A large GWAS of ECs identified several non-synonymous amino acid changes in the peptide binding pocket of HLA-B that are associated with the EC phenotype. Those mutations, however, were only responsible for ~20% of the observed effect, and it has been suggested that much rarer, 'private' mutations that would not be uncovered by even a larger GWAS are responsible for the majority of the EC phenotype. I wish to identify those rare genetic mutations that may be contributing to the exquisite control o HIV in ECs. To do so, I propose whole exome sequencing (WES) of genomic DNA from ECs. Our group has completed WES of ~24 ECs and already has several promising gene leads; we now wish to expand exome sequencing to dozens of other ECs throughout the U.S. and world. Patient populations include Ethiopians (in collaboration with investigators in Addis Ababa and Makele), Spaniards (from a large cohort of ECs that are substance users), Chinese, and U.S. Veterans (many of whom have substance use as their HIV acquisition risk factor). Candidate genes identified from WES will be subjected to in vitro functional studies. Importantly, we have identified a subset of ECs who have cell-intrinsic resistance to HIV. Those ECs will allow us to explore the genetics of elite control, with a focus on family studies, in order to determine inheritance patterns and causative genes. In the end I hope to have identified genetic factors responsible for host control of HIV.